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Updated: Jun 23, 2025
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity
Céline André1,2, Aurélie Bertaut3, Sylvain Ladoire4,5,6
1Unit of Pathology, Department of Tumor Biology and Pathology, Georges-François Leclerc Cancer Center, 21000 Dijon, France.
Background:
With the development of some new antibody-drug conjugates, the HER2 classification of breast carcinomas now includes the HER2-low (H2L) category: IHC 1+, 2+ non-amplified by ISH, and double-equivocal carcinomas, mostly luminal, expressing hormone receptors (HR+).
Methods:
We analyzed mutational status and transcriptomic activities of three HER2 effector pathways: PI3K-AKT, MAPK, and JAK-STAT, in association with clinicopathologic features, in 62 H2L carcinomas compared to 43 HER2-positive and 20 HER2-negative carcinomas, all HR+.
Results:
H2L carcinomas had significantly lower histoprognostic grades and mitotic and Ki67 proliferation indexes than HER2-positive carcinomas. Their PIK3CA mutation rates were close to those of HER2-negative and significantly higher than in HER2-positive carcinomas, contrary to TP53 mutations. At the transcriptomic level, we identified three distinct groups which did not reflect the new HER2 classification. H2L and HER2-negative carcinomas shared most of clinicopathological and molecular characteristics, except HER2 membrane expression (mRNA levels). The presence of a mutation in a signaling pathway had a strong pathway activation effect. PIK3CA mutations were more prevalent in H2L carcinomas, leading to a strong activation of the PI3K-AKT signaling pathway even in the absence of HER2 overexpression/amplification.
Conclusion:
PIK3CA mutations may explain the failure of conventional anti-HER2 treatments, suggesting that new antibody-drug conjugates may be more effective.
